PROJECT SUMMARY/ABSTRACT There is considerable evidence that homeostatic mechanisms stabilize the firing properties of neurons. Current models suggest that each neuron possesses a set of ion channels that endow it with cell-type specific firing properties. When faced with persistent genetic or pharmacological probations that disrupt excitability, neurons have been shown to rebalance ion channel expression to maintain stable firing properties. This phenomenon has been observed across diverse species, from Drosophila motoneurons to Xenopus central neurons and mouse cortical neurons. It is widely speculated that impaired or maladaptive homeostatic signaling will be directly relevant to neurological diseases including epilepsy, autism and Alzheimer's. However, direct connections to disease require an understanding the underlying molecular mechanisms. But, virtually nothing is known about the underlying molecular mechanisms that control the homeostatic modulation of ion channel expression and function in the nervous system of any organism. The goal of this proposal is to define some of the first known mechanisms for the homeostatic stabilization of neuronal excitability and ion channel function.